Method for production of pyrrolidinone derivatives

ABSTRACT

A compound represented by the following formula (12) useful as an intermediate for production of drug or agricultural chemical:                    
     (wherein R 21  to R 25  are each independently a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, a cyano group, a nitro group, an amino group, a carboxyl group, a thiol group, an alkylthio group of 1 to 4 carbon atoms or a carbamoyl group) can be produced by reacting a compound represented by the formula (13):                    
     (wherein R 21  to R 25  have the same definitions as given above) with 1,1-cyclopropanedicarboxylic acid. The compound of the formula (12) is useful as a raw material for production of a pyrrolidinone compound useful as an active ingredient of drug.

This application is a divisional of application Ser. No. 09/190,297,filed Nov. 13, 1998, and now U.S. Pat. No. 6,207,825 B1.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for production of apyrrolidinone compound which is useful as, for example, a remedy forcentral nervous system disorders (e.g. schizophrenia, dementia, manicdepressive psychosis, anxiety neurosis, drug poisoning and ischemicencephtalopathy), diseases associated with immunodeficiency andcryptorrhea, peptic ulcer, diabetes and complications thereof, glaucoma,etc.; a 3-carboxy-1-substituted-2-pyrrolidinone compound which is auseful intermediate for production of the above pyrrolidinone compound;and a process for production of the3-carboxy-1-substituted-2-pyrrolidinone compound.

2. Description of the Related Art

Pyrrolidinone compounds having a pyrrolidinone skeleton as the basicstructure, which are useful as, for example, a remedy for centralnervous system disorders (e.g. schizophrenia, dementia, manic depressivepsychosis, anxiety neurosis, drug poisoning and ischemicencephtalopathy), diseases associated with immunodeficiency andcryptorrhea, peptic ulcer, diabetes and complications thereof, glaucoma,etc., and processes for production of the compounds are disclosed in EPPublication No. 0668275A1 and Japanese Patent Application Kokai(Laid-Open) No. 40667/1997.

In producing the pyrrolidinone compounds according to the aboveprocesses, however, the number of steps is large and a reduction in thenumber of steps has been desired for the economic reason. There has alsobeen a problem of using a hydrogen-generating substance. There has alsobeen a problem that a corrosive substance must be used.

With respect to the process for production of a3-carboxy-1-phenyl-2-pyrrolidinone compound which is useful as anintermediate for production of the above pyrrolidinone compounds, thereare known, for example, a process by Danishefsky et al. described inOrg. Synth., 60, 66-71, 1981; and a process of hydrolyzing an estercompound obtained by a process described in Japanese Patent ApplicationKokai (Laid-Open) No. 40667/1997.

However, the former process uses, as a raw material,6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione which is expensive.Also, the latter process of hydrolyzing an ester compound is notpreferred for a safety reason because it may use a moisturesensitive/ignitive reagent in synthesis of the ester compound. None ofthese processes is satisfactory for industrial application.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a process for producingthe above pyrrolidinone compound useful as a pharmaceutically activeingredient, wherein the number of steps is smaller and neitherhydrogen-generating substance nor corrosive substance is used.

Another object of the present invention is to provide a process forproducing a 3-carboxy-1-phenyl-2-pyrrolidinone compound useful as anintermediate for production of the above pyrrolidinone compound usefulas a pharmaceutically active ingredient, without using any expensive rawmaterial.

Still another object of the present invention is to provide a processfor producing the 3-carboxy-1-phenyl-2-pyrrolidinone without using anymoisture sensitive/ignitive reagent.

The pyrrolidinone compound obtained by the present process isrepresented by the following formula (1):

wherein R¹ is an alkyl group of 1 to 12 carbon atoms or a substituentrepresented by the formula (2):

(wherein R² is a hydrogen atom, a halogen atom, an alkyl group of 1 to 4carbon atoms, an alkoxy group of 1 to 4 carbon atoms, a perfluoroalkylgroup of 1 to 4 carbon atoms, a hydroxyl group, a cyano group, an aminogroup, a nitro group, a carbamoyl group, a thiol group, an alkylthiogroup of 1 to 4 carbon atoms or a carboxyl group; p is an integer of 1to 5; when p is 2 or more, each R² independently has the same definitionas given above; and j is an integer of 0 to 2), and Q is a substituentrepresented by the formula (3a), (3b), (3c) or (3d):

{in the formula (3a), R³ and R⁴ are each independently a hydrogen atomor an alkyl group of 1 to 4 carbon atoms, and R³ and R⁴ may bond to eachother to form a morpholine ring; in the formula (3b), m and n are eachindependently an integer of 1 to 4, X is a hydrogen atom, a hydroxylgroup, a cyano group, a carbamoyl group, a halogen atom or an alkylgroup of 1 to 4 carbon atoms, and Y is a hydrogen atom, an alkyl groupof 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms,or a substituted or unsubstituted phenyl group; in the formula (3c), Wis an alkyl group of 1 to 4 carbon atoms, a substituted or unsubstitutedphenyl group, or an alkyl group of 1 to 2 carbon atoms substituted witha substituted or unsubstituted phenyl group; and in the formula (3d), mand n are each independently an integer of 1 to 4, Z is a hydrogen atom,an alkyl group of 1 to 18 carbon atoms, a substituted or unsubstitutedphenyl group, an alkyl group of 1 to 2 carbon atoms substituted with asubstituted or unsubstituted phenyl group, or a substituent representedby the formula (4):

—(CH₂)_(k)—OR⁵  (4)

(wherein k is an integer of 2 to 3; and R⁵ is a hydrogen atom, an alkylgroup of 1 to 3 carbon atoms, an alkenyl group of 2 to 3 carbon atoms oran alkynyl group of 2 to 3 carbon atoms)}.

The compound of the formula (1) is useful as, for example, a remedy forcentral nervous system disorders (e.g. schizophrenia, dementia, manicdepressive psychosis, anxiety neurosis, drug poisoning and ischemicencephtalopathy), diseases associated with immunodeficiency andcryptorrhea, peptic ulcer, diabetes and complications thereof, glaucoma,etc.

The present process for producing the pyrrolidinone compound of theformula (1) includes a step of reacting a compound represented by theformula (5):

(wherein R¹ has the same definition as given above) with an aminederivative represented by the formula (6a), (6b), (6c) or (6d):

{in the formula (6a), R³ and R⁴ have the same definitions as givenabove; in the formula (6b), X, Y, m and n have the same definitions asgiven above; in the formula (6c), W has the same definition as givenabove; and in the formula (6d) Z, m and n have the same definitions asgiven above) in the, presence of formaldehyde to produce a pyrrolidinonecompound of the formula (1).

The 3-carboxy-1-phenyl-2-pyrrolidinone compound which is useful as astarting material (an intermediate) for production of the pyrrolidinonecompound of the formula (1), is represented by the following formula(12) and is one of the compounds of the formula (5):

(wherein R²¹ to R²⁵ are each independently a hydrogen atom, a hydroxylgroup, a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxygroup of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbonatoms, a cyano group, a nitro group, an amino group, a carboxyl group, athiol group, an alkylthio group of 1 to 4 carbon atoms or a carbamoylgroup).

The compound of the formula (12) is useful as an intermediate forproduction of the pyrrolidinone compound of the formula (1) or as anintermediate for production of an agricultural chemical.

The compound of the formula (12) can be obtained by reacting a compoundof the formula (13):

(wherein R²¹ to R²⁵ have the same definitions as given above) with1,1-cyclopropanedicarboxylic acid.

According to the present invention, there can be provided a process forproducing a pyrrolidinone compound of the formula (1), wherein thenumber of steps is efficiently reduced and neither hydrogen-generatingsubstance nor corrosive substance is used.

According to the present invention, there can also be provided a3-carboxy-1-phenyl-2-pyrrolidinone compound which is useful as anintermediate for production of the pyrrolidinone compound of the formula(1); and a process for producing the 3-carboxy-1-phenyl-2-pyrrolidinonecompound without using any expensive raw material or without using anymoisture sensitive/ignitive reagent.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The production processes of the present invention are described indetail below.

The present process for production of the compound of the formula (1)includes, as mentioned previously, a step of reacting a compound of theformula (5) with one of the compounds of the formulas (6a) to (6d) inthe presence of formaldehyde.

Preferably in the present process, a pyrrolidinone compound of theformula (1) (wherein R¹ is a substituent represented by the formula(2a):

(wherein R^(2a) is a hydrogen atom or a halogen atom; p is an integer of1 to 5; when p is 2 or more, each R^(2a) independently has the samedefinition as given above; and j^(a) is 0), and Q is a substituentrepresented by the formula (7):

(wherein m and n are each independently an integer of 1 to 4; k is aninteger of 2 to 3; and R⁵ is a hydrogen atom, an alkyl group of 1 to 3carbon atoms, an alkenyl group of 2 to 3 carbon atoms or an alkynylgroup of 2 to 3 carbon atoms)}is produced by reacting a compound of theformula (5) {wherein R¹ is a substituent represented by the formula (2a)(wherein R^(2a), p and j^(a) have the same definitions as given above)}with an amine derivative represented by the formula (6d) {wherein Z is asubstituent represented by the formula (4) (wherein k and R⁵ have thesame definitions as given above)} in the presence of formaldehyde.

Also preferably in the present process, a pyrrolidinone compound of theformula (1) {wherein R¹ is a 4-chlorophenyl group and Q is a substituentrepresented by the formula (8):

(wherein R⁶ is an alkyl group of 1 to 3 carbon atoms)} is produced byreacting a compound of the formula (5) (wherein R¹ is a 4-chlorophenylgroup) with an amine derivative represented by the formula (9):

(wherein R⁶ has the same definition as given above) in the presence offormaldehyde.

The amine derivative represented by the formula (9) is preferably anamine derivative of the formula (9) wherein R⁶ is a methyl group.

In the general formula (1), “alkyl group of 1 to 3 carbon atoms” refersto a methyl group, an ethyl group, an n-propyl group or an isopropylgroup; “alkyl group of 1 to 4 carbon atoms” refers to each groupmentioned above, an n-butyl group, a sec-butyl group, a tert-butylgroup, an isobutyl group or the like; “alkyl group of 1 to 12 carbonatoms” refers to each group mentioned above, a pentyl group, a hexylgroup, a heptyl group, an octyl group, a nonyl group, a decyl group, anundecyl group, a dodecyl group or the like; “alkyl group of 1 to 18carbon atoms” refers to each group mentioned above, a tridecyl group, atetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecylgroup, an octadecyl group or the like; “alkenyl group of 2 to 3 carbonatoms” refers to a vinyl group, an allyl group, a 1-propenyl group, anisopropenyl group or the like; “alkynyl group of 2 to 3 carbon atoms”refers to an ethynyl group, a 1-propynyl group, a 2-propynyl group orthe like; “halogen atom” refers to a fluorine atom, a chlorine atom, abromine atom or an iodine atom; “alkoxy group of 1 to 4 carbon atoms”refers to a methoxy group, an ethoxy group, an n-propoxy group, anisopropoxy group, a butoxy group or the like; “perfluoroalkyl group of 1to 4 carbon atoms” refers to a trifluoromethyl group, a pentafluoroethylgroup, a heptafluoropropyl group, a nonafluorobutyl group or the like;“alkylthio group of 1 to 4 carbon atoms” refers to a methylthio group,an ethylthio group, a propylthio group, a butylthio group or the like;“substituted phenyl group” refers to a phenyl group substituted with ahalogen atom(s), an alkyl group(s) of 1 to 4 carbon atoms, an alkoxygroup(s) of 1 to 4 carbon atoms, a perfluoroalkyl group(s) of 1 to 4carbon atoms or the like; and “alkyl group of 1 to 2 carbon atomssubstituted with a phenyl group” refers to a benzyl group, a phenethylgroup or the like.

The production route of the present invention for the compound of theformula (1) is shown by the following reaction formula (1)

{wherein R¹ and Q have the same definitions as in the general formula(1); and 6a, 6b, 6c and 6d have the same definitions as in the generalformulas (6a) to (6d)}.

As the formaldehyde used in the reaction of the reaction formula (1),there can be mentioned paraformaldehyde, trioxane, aqueous solutionsthereof, etc. The aqueous solution ordinarily has a concentration of 5to 50% by weight. The formaldehyde is used in an amount of 1 to 10 molesper mole of the compound of the general formula (5).

As the solvent used in the reaction, there can be mentioned water;alcohols such as methanol, ethanol, isopropanol, butanol and the like;ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycoldimethyl ether and the like; aromatic hydrocarbons such as benzene,toluene and xylene and the like; halogen-containing hydrocarbons such asdichloromethane, dichloroethane, chloroform and the like; acetonitrile;and so forth. These solvents can be used singly or in admixture. Thereaction may be conducted without using any solvent.

The reaction temperature may range from 0° C. to the boiling point ofthe solvent used, preferably from room temperature to 150° C.

The reaction time is not particularly restricted, but is preferably 1 to48 hours.

There is no particular restriction as to the order of mixing thecompound of the general formula (5), the amine derivative of the generalformula (6a), (6b), (6c) or (6d) and formaldehyde. They are mixed at onetime; or, the amine and formaldehyde are mixed first and then thecompound of the general formula (5) is added; or, the compound of thegeneral formula (5) and formaldehyde are mixed first and then the amineis added.

In the reaction of the reaction formula (1), there is a case when a3-methylene form of the compound of the formula (5), represented by thefollowing general formula (10):

{wherein R¹ has the same definition as in the general formula (1)} isformed as an intermediate. This intermediate may be reacted with theamine of the general formula (6a), (6b), (6c) or (6d).

This reaction may be conducted in an equimolar ratio. The amine may beused in excess.

As the solvent used in the reaction, there can be mentioned water;alcohols such as methanol, ethanol, isopropanol, butanol and the like;ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycoldimethyl ether and the like; aromatic hydrocarbons such as benzene,toluene and xylene and the like; halogen-containing hydrocarbons such asdichloromethane, dichloroethane, chloroform and the like; ketones suchas acetone, methyl ethyl ketone and the like; acetonitrile; and soforth. These solvents can be used singly or in admixture. The reactionmay be conducted without using any solvent.

The reaction temperature may range from 0° C. to the boiling point ofthe solvent used, preferably from room temperature to 150° C.

The reaction time is not particularly restricted, but is preferably 1 to48 hours.

In the post-treatment after the above reaction, a purification methodordinarily used, such as column chromatography, recrystallization or thelike can be used.

The compound of the formula (5) is preferably a compound of the formula(5) wherein R¹ is represented by the formula (2) (wherein R² and p havethe same definitions as given above, and j is 0), or a salt thereof;more preferably a compound of the formula (5) wherein R¹ is a4-chlorophenyl group.

The compound of the formula (5) can be obtained by a known process, forexample, by hydrolyzing, with an acid or an alkali, a compound of thegeneral formula(11):

(wherein R¹ has the same definition as in the formula (1), and A is analkyl group of 1 to 4 carbon atoms, a substituted or unsubstitutedphenyl group, or an alkyl group of 1 to 2 carbon atoms substituted witha substituted or unsubstituted phenyl group), the compound of theformula (11) being obtained by a process described in EP Publication No.0668275A1 or Japanese Patent Application Kokai (Laid-Open) No.40667/1997.

In the above reaction, there can ordinarily be used, as the acid, aninorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acidor the like; and there can be mentioned, as the alkali, sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate,potassium carbonate, etc.

The amount of the acid or alkali used is 0.1 to 100 moles, preferably 1to 10 moles per mole of the compound of the formula (11).

The reaction may be conducted in the presence of a phase-transfercatalyst.

As the solvent used in the reaction, there can be mentioned water;alcohols such as methanol, ethanol, isopropanol, butanol and the like;ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycoldimethyl ether and the like; aromatic hydrocarbons such as benzene,toluene and xylene and the like; halogen-containing hydrocarbons such asdichloromethane, dichloroethane, chloroform and the like; acetonitrile;and so forth. These solvents can be used singly or in admixture.

The reaction temperature may range from 0° C. to the boiling point ofthe solvent used, preferably from room temperature to 150° C.

The reaction time is not particularly, restricted, but is preferably 1to 48 hours.

The carboxylic acid obtained can be used in the next reaction as it isor in the form of a salt thereof.

A compound of the following formula (12) as one of the compounds of theformula (5):

(wherein R²¹ to R²⁵ are each independently a hydrogen atom, a hydroxylgroup, a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxygroup of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbonatoms, a cyano group, a nitro group, an amino group, a carboxyl group, athiol group, an alkylthio group of 1 to 4 carbon atoms or a carbamoylgroup) can be obtained by reacting a compound represented by the formula(13):

{wherein R²¹ to R²⁵ have the same definitions as in the formula (12)}with 1,1-cyclopropanedicarboxylic acid.

This process, as compared with the known process mentioned above, has amerit in using neither expensive raw material nor moisturesensitive/ignitive reagent.

In the above process, it is preferred that R²¹, R²², R²⁴ and R²⁵ areeach a hydrogen atom and R²³ is a chlorine atom or a bromine atom; andit is more preferred that R²¹, R²², R²⁴ and R²⁵ are each a hydrogen atomand R²³ is a chlorine atom.

In the formulas (12) and (13), the halogen atom includes a fluorineatom, a chlorine atom, a bromine atom and an iodine atom.

As the lower alkyl group of 1 to 4 carbon atoms, there can be mentioned,for example, a methyl group, an ethyl group, an n-propyl group, anisopropyl group, an n-butyl group, an isobutyl group, a sec-butyl groupand a tert-butyl group.

As the lower alkoxy group of 1 to 4 carbon atoms, there can bementioned, for example, a methoxy group, an ethoxy group, a propoxygroup, an isopropoxy group, an n-butoxy group, an isobutoxy group, asec-butoxy group and a tert-butoxy group.

As the perfluoroalkyl group of 1 to 4 carbon atoms, there can bementioned, for example, a trifluoromethyl group, a pentafluoroethylgroup, a heptafluoropropyl group, a heptafluoroisopropyl group and anonafluorobutyl group.

As the lower alkylthio group of 1 to 4 carbon atoms, there can bementioned, for example, a methylthio group, an ethylthio group, ann-propylthio group, an isopropylthio group, an n-butylthio group, anisobutylthio group, a sec-butylthio group and a tert-butylthio group.

The reaction of the compound of the formula (13) with1,1-cyclopropanedicarboxylic acid can be conducted in the presence orabsence of a solvent. As the solvent, there can be mentioned aromatichydrocarbons such as benzene, toluene, xylene and the like; ethers suchas diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,ethylene glycol dimethyl ether and the like; alcohols such as methanol,ethanol, propanol and the like; aprotic polar solvents such asdimethylformamide, dimethyl sulfoxide and the like; halogen-containingsolvents such as methylene chloride, chloroform, dichloroethane and thelike; carboxylic acid esters such as ethyl acetate, ethyl propionate andthe like; carboxylic acids such as formic acid, acetic acid, propionicacid and the like; water; acetone; methyl ethyl ketone; andacetonitrile. These solvents can be used singly or in admixture.

The proportions of the compound of the formula (13) and1,1-cyclopropanedicarboxylic acid should be determined in view of theirreactivity, the formation of by-products and the economy of thereaction; however, the compound of the formula (13) is used in an amountof generally 0.1 to 10 moles, preferably 0.3 to 3 moles, more preferably0.6 to 1.5 moles per mole of 1,1-cyclopropanedicarboxylic acid.

The reaction temperature, when a solvent is used, may range from aboutroom temperature to the reflux temperature, preferably from 60° C. to100° C., more preferably from 70° C. to 95° C. and, when no solvent isused, may range from about room temperature to about the melting pointof reaction substrates used.

EXAMPLES

The present invention is described more specifically below withreference to Examples. However, the present invention is not restrictedby these Examples.

Example 1 Production of 3-carboxy-1-(4-chlorophenyl)-2-pyrrolidinone

2.0 g of 1,1-cyclopropanedicarboxylic acid and 2.9 g of 4-chloroanilinewere added to 2.7 g of water. The mixture was stirred at 80° C. for 20hours.

To the reaction mixture were added 20 ml of a 25% aqueous NaOH solutionand 20 ml of ethyl acetate, followed by thorough stirring. The aqueouslayer was washed with ethyl acetate and then made acidic withhydrochloric acid. The resulting crystals were collected by filtration,then washed with water, and dried to obtain 2.2 g of an intendedcompound at a yield of 59.7%.

Melting point: 170° C. (decomposed)

¹H-NMR (DMSO, δ ppm): 2.2-2.4 (2H,m), 3.61 (1H,t), 3.8-3.95 (2H,m),7.4-7.5 (2H,m), 7.65-7.75 (2H,m)

Example 2 Production of 1-(4-bromophenyl)-3-carboxy-2-pyrrolidinone

30 g of 1,1-cyclopropanedicarboxylic acid and 50 g of 4-bromoanilinewere added to 50 ml of acetonitrile, followed by refluxing for 7 hourswith heating and stirring.

The reaction mixture was subjected to solvent removal under reducedpressure. To the residue were added an aqueous sodium hydrogencarbonatesolution and ethyl acetate, and the mixture was stirred thoroughly. Theaqueous layer was washed with ethyl acetate, then made acidic withhydrochloric acid, and subjected to extraction with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The resulting concentrate wassludged with diethyl ether to obtain 32.8 g of an intended compound at acrude yield of 50.2%.

¹H-NMR (CDCl₃, δ ppm): 2.39-2.68 (2H,m), 3.66 (1H,t), 3.85 (2H,m), 7.51(4H,s)

Example 3 Production of3-carboxy-1-(3-trifluoromethylphenyl)-2-pyrrolidinone

10.0 g of 1,1-cyclopropanedicarboxylic acid and 12.4 g of4-trifluoromethylaniline were added to 15 ml of acetonitrile, followedby refluxing for 7 hours with heating and stirring. The subsequentoperation was conducted in the same manner as in Example 2 to obtain 7.1g of an intended compound at a yield of 38.8%.

¹H-NMR (CDCl₃, δ ppm): 2.43-2.67 (2H,m), 3.73 (1H,t), 3.97 (2H,t),7.47-7.54 (2H,m), 7.75-7.87 (2H,m)

Reference Example 1 Production of3-carboxy-1-(4-chlorophenyl)-2-pyrrolidinone

61.8 g of 1-(4-chlorophenyl)-3-ethoxycarbonyl-2-pyrrolidinone was mixedwith 45 g of ethanol. Thereto was added-a solution of 46.1 g of sodiumhydroxide dissolved in 100 ml of water, followed by mixing. The mixturewas once made into a complete solution, after which a large amount ofcrystals appeared.

Thereto was added water. The crystals were collected by filtration andwashed with diethyl ether. To the filtrate was added diethyl ether,followed by stirring. The aqueous layer was separated. This aqeuouslayer and the crystals were combined and made acidic with hydrochloricacid with thorough stirring. The crystals were collected by filtrationand washed with water to obtain 52.5 g of3-carboxy-1-(4-chlorophenyl)-2-pyrrolidinone.

Melting point: 170° C. (decomposed)

¹H-NMR (DMSO, δ ppm): 2.2-2.4 (2H,m), 3.61 (1H,t), 3.8-3.95 (2H,m),7.4-7.5 (2H,m), 7.65-7.75 (2H,m)

This spectrum data corresponded with that of the compound obtained byreacting p-chloroaniline with6,6-dimethyl-5,7-dioxyaspiro[2,5]octane-4,8-dione according to themethod described in Org. Synth., 60, 66-71, 1981.

Example 4 Production of1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone

3.0 g of 1-(4-chlorophenyl)-3-carboxy-2-pyrrolidinone and 2.32 g of4-(2-methoxyethyl)piperazine were mixed with 6 ml of methanol. Theretowas added 0.465 g of 80% paraformaldehyde. The mixture was subjected toa reaction for 10.5 hours under refluxing and then cooled to roomtemperature. Thereto was added 10 ml of methanol, and the insolubleswere removed by filtration. The filtrate was concentrated under reducedpressure. The residue was mixed with 15 ml of water. The resultingcrystals were collected by filtration and washed with 3 ml of 95%aqueous methanol twice to obtain 3.42 g of1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone.

Melting point: 103-105° C.

¹H-NMR (CDCl₃, δ ppm): 2.01-2.12 (1H,m), 2.29-2.62 (12H,m), 2.78-2.94(2H,m), 3.35 (3H,s), 3.51 (2H,t), 3.74-3.80 (2H,m), 7.32 (2H,d), 7.59(2H,d)

Reference Example 2 Production of1-(4-chlorophenyl)-3-methylene-2-pyrrolidinone

1.56 g of 1-(4-chlorophenyl)-3-carboxy-2-pyrrolidinone was mixed with 7ml of methanol. Thereto were added 0.26 g of 75% paraformaldehyde and0.75 g of 4-methoxypiperidine. The mixture was refluxed for 2 hours. Thereaction mixture was concentrated to dryness. The residue was purifiedby silica gel column chromatography using chloroform (a solvent) toobtain 0.85 g of 1-(4-chlorophenyl)-3-methylene-2-pyrrolidinone.

Melting point: 119-120° C.

¹H-NMR (CDCl₃, δ ppm): 2.87-2.94 (2H,m), 3.83 (2H,t), 5.46 (1H,t), 6.14(1H,t), 7.32-7.37 (2H,m), 7.67-7.73 (2H,m)

Reference Example 3 Production of1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone

0.85 g of 1-(4-chlorophenyl)-3-methylene-2-pyrrolidinone and 0.71 g of4-(2-methoxyethyl)piperazine were mixed with 3 ml of acetonitrile. Themixture was refluxed for 3.5 hours. The reaction mixture wasconcentrated to dryness. The residue was purified by silica gel columnchromatography using a mixed solvent (chloroform/methanol=20/1) toobtain 1.1 g of1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone.

Melting point: 103-105° C.

¹H-NMR (CDCl₃, δ ppm): 2.01-2.12 (1H,m), 2.29-2.62 (12H,m), 2.78-2.94(2H,m), 3.35 (3H,s), 3.51 (2H,t), 3.74-3.80 (2H,m), 7.32 (2H,d), 7.59(2H,d)

Reference Example 4 Production of1-(4-bromophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone

1.31 g of 1-(4-bromophenyl)-3-methylene-2-pyrrolidinone and 1.00 g of4-(2-methoxyethyl)piperazine were mixed with 5 ml of ethylene glycoldimethyl ether. The mixture was refluxed for 6.5 hours and then cooled.Thereto was added water. The mixture was subjected to extraction withethyl acetate twice. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated to obtain 1.91 g of1-(4-bromophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone.

¹H-NMR (CDCl₃, δ ppm): 1.98-2.12 (1H,m), 2.29-2.41 (1H,m), 2.53-2.63(11H,m), 2.78-2.94 (2H,m), 3.35 (3H,s), 3.51 (2H,t), 3.74-3.82 (2H,m),7.46 (2H,d), 7.54 (2H,d)

Reference Example 5 Production of1-(4-bromophenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]methyl-2-pyrrolidinone

1.31 g of 1-(4-bromophenyl)-3-methylene-2-pyrrolidinone and 2.00 g of4-(2-methoxyphenyl)piperazine were mixed with 5 ml of ethylene glycoldimethyl ether. The mixture was refluxed for 2 hours and then cooled.Thereto was added water. The mixture was subjected to extraction withethyl acetate twice. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated to obtain an oily material. Theoily material was purified by silica gel column chromatography using amixed solvent of chloroform/methanol=40/1 to obtain 1.88 g of oily1-(4-bromophenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]methyl-2-pyrrolidinone.

¹H-NMR (CDCl₃, δ ppm): 2.03-2.17 (1H,m), 2.34-2.46 (1H,m), 2.60-3.20(11H,m), 3.70-3.89 (2H,m), 3.87 (3H,s), 6.85-7.04 (4H,m), 7.45-7.59(4H,m)

Reference Example 6 Production of1-(4-bromophenyl)-3-pyrrolidinomethyl-2-pyrrolidinone

There were mixed 1.31 g of1-(4-bromophenyl)-3-methylene-2-pyrrolidinone, 2.00 g of4-(2-methoxyphenyl)piperazine and 5 ml of pyrrolidine. The mixture wasrefluxed for 1 hour and then cooled. Thereto was added water. Themixture was subjected to extraction with ethyl acetate twice. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography using a mixed solvent of chloroform/methanol=40/1 toobtain 1.79 g of 1-(4-bromophenyl)-3-pyrrolidinomethyl-2-pyrrolidinone.

¹H-NMR (CDCl₃, δ ppm): 1.74-1.84 (4H,m), 2.01-2.15 (1H,m), 2.34-2.45(1H,m), 2.51-2.88 (6H,m), 2.94-3.00 (1H,m), 3.75-3.80 (2H,m), 7.46(2H,d), 7.55 (2H,d)

What is claimed is:
 1. A process for producing a compound represented bythe formula (12):

wherein R²¹ to R²⁵ are each independently a hydrogen atom, a hydroxylgroup, a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxygroup of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbonatoms, a cyano group, a nitro group, an amino group, a carboxyl group, amercapto group, an alkylthio group of 1 to 4 carbon atoms or a carbamoylgroup, which process includes a step of reacting a compound representedby the formula (13):

wherein R²¹ to R²⁵ have the same definitions as given above with1,1-cyclopropanedicarboxylic acid to produce a compound of the formula(12).
 2. A process according to claim 1, wherein R²¹, R²², R²⁴ and R²⁵are each a hydrogen atom and R²³ is a chlorine atom or a bromine atom.3. A process according to claim 2, wherein R²³ is a chlorine atom.